1. Field of the Invention
The present invention relates to new derivatives of physostigmine, to processes for their production and to novel pharmaceutical compositions and dosage forms containing them. The invention further relates to the therapeutic use of the novel physostigmine derivatives of the invention in the treatment of syndromes related to changes in cerebral metabolism in the elderly.
2. Description of Related Art
Physostigmine (I) is a well-known alkaloid which has been used as a myotic agent since the beginning of this century. The substance has now almost completely been abandoned for its original therapeutic use. However over the last 15 years it has been found that physostigmine's significant anticholinesterase activity makes it particularly valuable in the treatment of Alzheimer's disease and the severe effects of various forms of senile dementia, since it improves the cholinergic deficit found in the brain of affected patients. ##STR1##
A number of clinical studies (Davis, Am. J. Psychiat., 139, 1421, 1982; Jotkowitz, Ann. Neurol., 14, 690, 1983; Davis, New Engl. J. Med., 308, 721, 1983) have shown that the intravenous administration of repeated daily doses of physostigmine produced significant improvements in memory. It was also found that when the alkaloid is administered subcutaneously or by mouth, it is degraded rapidly, with the result that treatment must be repeated at short intervals. A further disadvantage of both the intravenous and subcutaneous routes of administration is that both are uncomfortable and impractical for use over long periods.
It is known that physostigmine is capable of passing through the blood-brain barrier to reach the nuclei where it exerts its effect. The physostigmine derivatives currently used for this purpose include salts such as those traditionally described in pharmacopeias for formulating basic alkaloids. These include the salicylate, the sulphate or the nitrate, though more lipophilic derivatives of physostigmine, such as the heptyl derivative (IT 047780) or its analogues have been developed.
Other derivatives include those described in EP-A-0 298 202. This document describes derivatives of physostigmine in which the methyl carbamate group is replaced by a C.sub.2-12 alkyl carbamate group and claims organic salts of such derivatives with organic acids selected from tartaric, maleic and citric acids.
A further class of physostigmine derivatives are described in U.S. patent application Ser. No. 07/166,824, made publicly available by the Department of Health and Human Services through the National Technical Information Service, including (-)-N(1)-norphysostigmine, (-)-N(1)-alkylphysostigmine and (-)-N(1)-phenylethylphysostigmine.
The compounds of application Ser. No. 07/166,824 are represented by the formula ##STR2## wherein R.sup.1 =H, R.sup.2 .dbd.CH.sub.3
R.sup.1 =Bz, R.sup.2 .dbd.CH.sub.3 PA1 R.sup.1 =Bz, R.sup.2 .dbd.OH PA1 R.sup.1 =Bz, R.sup.2 .dbd.OCONH--CH.sub.3 PA1 R.sup.1 =H, R.sup.2 .dbd.CONH--CH.sub.3 PA1 R.sup.1 =CH.sub.2 .dbd.CH--CH.sub.2, R.sup.2 .dbd.CONHCH.sub.3 PA1 R.sup.1 =CH.sub.2 --CH.sub.2 --Ph, R.sup.2 .dbd.CONHCH.sub.3.
JP-0-1279830 discloses the use of physostigmine-containing compositions wherein pentaenoic and/or hexaenoic acids and phosphatidyl choline are included as excipients.
A disadvantage of the salts of physostigmine and the derivatives and compositions described hitherto is that they have an extremely short half-life and are eliminated from the blood completely within 2 hours. Physostigmine is also a highly toxic product with a small therapeutic margin, and the doses administered by conventional routes must therefore necessarily be low. We have now attempted to rationalize the use of physostigmine by devising new salts and also by administering the drug in such a way that it gains a more direct access to the brain for prolonged periods in non-toxic concentrations. In making this invention, it was surprisingly found that certain lipophilic salts of physostigmine, which are specifically the subject of the invention, when administered in an appropriate manner, can prolong the mean life of the alkaloid, so bringing significant therapeutic advantages.